5-benzyl pyrimidines intermediates therefore,and method

ABSTRACT

1. THE METHOD OF PREPARING A COMPOUND OF FORMULA I   2,4-DI(H2N-),5-((R1,R2,R3,R4-PHENYL)-CH2-)-PYRIMIDINE   COMPRISING THE STEP OF REACTING A COMPOUND OF FORMULA II   R1,R2,R3,R4-PHENYL-CH2-C(-CN)=CH-N(-R5)-R6   WITH GUANIDINE CARBONATE IN A POLAR APROTIC SOLVENT AT AN ELEVATED TEMPERATURE ABOVE ROOM TEMPERATURE TO ABOUT 160* C. WHEREIN R1-R4 ARE THE SAME OR DIFFERENT, AND EACH IS HYDROGEN, HALOGEN, LOWER ALKYL, LOWER ALKOXY OR BENZYLOXY, OR R3 AND R4 TAKEN TOGETHER MAY BE METHYLENEDIOXY WHEN BOTH R1 AND R2 ARE HYDROGEN, AND WHEREIN NR5R6 IS PRIMARY AMINO OR SECONDARY AMINO OF NOT LESS THAN ONE OR MORE THAN TWELVE CARBON ATOMS SELECTED FROM THE GROUP CONSISTING OF MONOALKYLAMINO, DIALKYLAMINO, ANILINO OR NAPHTHYLAMINO WHEREIN THE PHENYL OR NAPHTHYL THEREOF MAY BE SUBSTITUTED WITH ONE OR MORE POSITIONS WITH LOWER ALKYL, LOWER ALKOXY AND HALOGEN, NETHYLENILINO, PYRROLIDINO, PIPERIDINO N-METHYLANILINO, PIPERAZINO, BENZYLAMINO AND MORPHOLINO, AND WHEREIN THE LOWER ALKYL AND LOWER ALKOXY ARE EACH OF 1 TO 4 CARBON ATOMS.

United States Patent US. Cl. 260-256.4 N 8 Claims ABSTRACT OF THEDISCLOSURE The method of preparing substituted or unsubstitutedbenzylpyrimidine compounds by reacting guanidine carbonate in an aproticsolvent at an elevated temperature with a compound of the formulawherein NR R is a primary amino or secondary amino group of not lessthan one or more than twelve carbon atoms and R -R are the same ordifferent and each is hydrogen, halogen, lower alkyl, lower alkoxy orbenzyloxy group, or R and R taken together may be methylendioxy whenboth R and R are hydrogen.

This is a division, of application Ser. No. 16,606, filed on Mar. 4,1970 now U.S. Pat. No. 3,697,512, issued Oct 10, 1972.

This invention relates to improved methods of preparingS-benzylpyrimidines and more particularly is related to a class ofstable a-benzylacrylonitrile intermediates, and to methods of makingsuch compounds.

2,4-Diamino-5 benzylpyrimidines possess both antimalarial andantibacterial activities (J. Am. Chem. Soc, 1951, 73, 3758). Maximalantibacterial activity is found among derivatives which bear electrondonating substituents in the benzene nucleus and are unsubstituted inthe 6th position of the pyrimidine moiety, 2,4-Diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine or trimethoprim (US. Pat. 2,909,522)has a moderately broad antibacterial spectrum which includes many of theGram-positive species but it is also active against species of the genusProteus. In common with other 2,4-diaminopyrimidines it is a competitorof folic and folinic acids in microorganisms which require thesenutrilites, and it can be shown to inhibit dihydrofolate reductase inStreptococcus faecalis. A strong potentiative effect is observed whenthe drug is administered in combination with sulphonamides as aconsequence of the sequential blockade of the biochemical pathway whichleads to the de novo synthesis of 00cmzymes F. This potentiation may bedemonstrated both in vitro and in experimental infections in mice withStaphyloccoccus and Proteus species.

2,4-Diamino 5 benzylpyrimidines, which includes trimethoprim and2,4-diamino-5-(3,4-dimethoxybenzyl) pyrimidine or diaveridine and2,4-diamino 5 (3,4'dimethoxy-S bromobenzyl)pyrimidine (U.S. Pat. 2,658,-897), may be administered orally at a dose of 1 mg./kg. to 30 mg./kg.per day.

Preferably these compounds are administered in tablet form to a mammalbeing treated, and trimethoprim may advantageously be combined withsulphamethoxazole against certain respiratory infections. A furtherexample of this class is 2,4-diamino-5-(2-methy1-4',5'-dimethoxybenzyl)pyrimidine (ormetoprim) which has been reported to show antibacterialactivity, and also has coccidiostatic properties when combined withsulphadimethoxine.

A new route was developed some years ago for the preparation of2,4-diamino-5-benzylpyrimidines (see Stenbuck, Baltzly and Hood, J. Org.Chem- 1963, 28, 1983 and British Patent Specification No. 957,797). Thisroute comprises the steps of (i) condensing an aromatic aldehyde with a,B-substituted propionitrile in the presence of both an alcohol assolvent and a strong base to give a mixture of isomers of formulae (Ia)and (Ib) respectively:

AZCHO Cl-l CN) ArCH I C' CN A CH C wherein Ar is an optionallysubstituted phenyl group, Y is an alkoxy, thioalkyl or dialkylaminogroup, and Z is the group Y or is an alkoxy group derived from thesolvent alcohol; and (ii) reacting either the pure benzal isomer (Ia) ora mixture of benzal and benzyl isomers (Ia) and (Ib) respectively withguanidine to give a 5- benzylpyrimidine of formula Although it was knownthat the intermediate product obtained in the first step was a mixtureof isomers of formulae (Ia) and (b), only the (Ia) benzal isomer couldbe isolated in a crystalline form after some purification steps. The twoisomers were assumed to be in equilibrium with each other when preparedunder alkaline conditions and further reacted with guanidine accordingto the aforesaid disclosures, but it was not clearly established whichof the isomers was primarily interacting in the second step. In manycases this method affords acceptable yields but in certain instancesextensive losses (up to about half the material used) ensue fromformation of yellow polymers.

The further conversion of composite mixtures of derivatives and isomersaccording to British Patent Specification No. 957,797, aiiorded therequired 2,4-diamino-5- benzylpyrimidines only in yields between 25 and45%, and in view of the importance of the final products and thedifficulties with by-products and impurities, alternative methods werealso explored by various investigators. For instance, the specificationof South African Patent Application No. 65/5,794 discloses a processcomprising the steps of (a) reacting acetylthymine withN-bromosuccinimide to form acetylbromothymine, (b) condensing theproduct with a substituted benzene, (c) reacting the prod net with ahalogenating agent, and (d) aminating the halogeno derivative. However,this process suifers from the disadvantages that acetylbromothymine isexpensive to make, condensation with the benzene compound does notprovide the further intermediate in a high yield, and the last stagerequires operation under pressure and usually results in an equilibriumstate with consequent poor yields. Altogether the process requires fourstages to obtain the final product, and none of the stages is particucucu AtCl-l C-\ 63 M CHOMe LICK-C MeOl-X excess NaOMe JtrCl-l CH (11) Whenthe acetal (II) is subsequently treated with guanidine in alcoholicsolution, the alkaline condition is thought to catalyse thereconstitution of the double bond, initially in the form of (I'b), andthe intermediate can thus react wtih guanidine to givet he desiredS-benzylpyrimidine.

Acetals of formula (II) may also be prepared by condensing thecorresponding aromatic aldehyde with a 3,3- dialkoxypropionitrile andreducing, preferably catalytically, the 3,3 dialkoxy 2benzalpropionitrile interme diate so obtained. (See US. Pat. 3,487,083.)

The aforesaid British Patent Specification No. 957,797 also describes(Example 14) the reaction of veratraldehyde with[i-dimethylaminopropionitrile in the presence of sodium in ethanol togive a mixture of fi-dimethylaminoveratralnitrile (III) andB-ethoxyveratralnitrile (IV) in a 32% yield.

MeO (III) 0N MeO- -crr=o (lH NMez MeO (1v) ON MeO- on=o ornom It isstated in the Example that this mixture was subsequently cyclised withguanidine to give 2,4-diamino--(3', 4-dimethoxybenzyl)-pyrimidine. It isto be noted that both the compounds (III) and (IV) above are benzalderivatives.

It has now been found that N-substituted e-amino-abenzylacrylonitrilesof the configuration of formula (V) can be prepared remarkably readilyunder a conveniently wide variety of conditions and that the products soobtained are not only substantially free of contamination with thecorresponding banzal isomer but manifest an unexpected stability andcapability of maintaining their configuration.

The benzyl configuration of these compounds shows little or no tendencyto isomarise into the benzal form prepared and exemplified in theBritish Patent Specification No. 957,797. Furthermore, thefi-amino-a-benzylacrylonitriles can be converted into benzylpyrimidinesor into other benzyl derivatives, which may be used as preferred for thepreparation of benzylpyrimidines or other heterocyclic ring systems.

According to the present invention in one aspect therefore there isprovided an N-substituted-B-amino-u-benzylacrylonitrile compound of theformula (V), in a form substantially free from contamination with thefi-amino-otbenzylidenepropionitrile isomer. In particular thecontamination with the benzal isomer is normally substantially below10%, taken as a percentage of the amount of compound of formula (V), andpreferably below 5 or, still better, below 2%. Usually the best methodsfor making the compound of formula (V) provide the product with lessthan 0.5% contamination and frequently no bcnzal isomer can be detectedat all with analytical methods sensitive to even as low as 0.33%admixture. It has, on the other hand, been observed that contaminationat or above the 10% level adversely affects the yield and quality of thefinal benzylpyrimidine product, and the appearance of purple or yellowdiscolourisation may ag gravate the diificulties, especially isolationin a pure form, an essential requirement when the product is to be usedclinically, there therefore being necessary many tedious, time-consumingand accordingly expensive purification steps.

As previously defined Ar is an optionally substituted phenyl group informula (V). The fi-amino group NR R is an aliphatic, heterocyclic oraromatic amino group, and can have only one hydrogen atom for R and R Ingeneral it may be stated that, as a free amine, HNR R is preferred tohave a pKa value not lower than about 0, and also most preferably nothigher than about 6.

In particular, it is especially preferred that the NR R group is aprimary anilino group (e.g. aniline, oand ptoluidine p-anisidine,p-chloroaniline, 2,5 and 3,4-dichloroanilines). The phenyl ring of thisgroup may be optionally substituted with one or more substituents suchas halogen atoms, and alkyl and alkoxy groups, but the unsubstitutedanilino group is, however, particularly preferred.

The NR R group may also be a primary amino group other than theaforesaid primary anilino group, such as a monoalkylamino, benzylamino,or naphthylamino, preferably a-fi-naphthylamino group; or may be asecondary amino group, such as a dialkylamino, N-ethyl-anilino,pyrrolidino, piperidino, N-methylanilino or a piperazino group, or mostpreferably the morpholino group.

In particular the invention provides compounds of formula (VIII), in aform substantially free from contamination with the,8-amino-4-benzylidene-propionitrile isomer, as hereinbefore defined:

R (VIII) wherein the group NR R is as hereinbefore defined withreference to a compound of formula (V), and R R R and R are the same orditferent and each is a hydrogen or a halogen atom, an alkyl, alkoxy, orbenzyloxy group, or R and R taken together may be a methylenedioxy groupwhen both R and R are hydrogen atoms. Preferably the whole amino groupNR R comprises not more than 12 carbon atoms.

All of the above compounds of formula VIII are convertible to benzylpyrimidines and such pyrimidines are useful as antibacterials.

In formulae (V) and (VIII), and elsewhere in this application each ofthe alkyl or alkoxy groups in the sub stituents may have from 1 to 4carbon atoms, e.g. they may be methyl, ethyl, propyl or butyl groups,including normal, iso or tertiary branched forms, and correspondingalkoxy groups. Each of the halogen atoms may be represented by achlorine, bromine, fluorine or iodine atom.

More particularly the para-position of the phenyl group may besubstituted with a benzyloxy, but preferably an alkoxy group, such as amethoxy group, especially with a similar or identical alkoxysubstitution at one or advantageously both adjacent positions on thepheny ring. As another possibility alkoxy, e.g. methoxy substitution, insuch positions may be combined with an alkyl, e.g. methyl, substitutionat the ortho-position of the phenyl group.

The compounds of formulae V (or VIII) fall into two classes A and Bdependent on their reactivity towards guanidine.

cu s HNHPh VIIIA Wherein Ph is an aryl group of 6 to 12 carbon atomswhich may be substituted in one, two or three positions with loweralkyl, lower alkoxy, and halogen, preferably chlorine and where the R -R4 are as defined previously and lower alkyl halogen and lower alkoxy areas previously defined. Compounds of the type VIIIA react with guanidinein e.g. solvent lower alcohol solution to form2,4-diamino-S-benzylpyrimidines in good yield. Advantageously thereaction is conducted at the refiux temperature of the solution, butuseful rates are found at lower temperatures down to room temperatures.These compounds are consequently preferred.

The compounds of formula VIIIB wherein R is alkyl or aryl and R is alkyland may also be hydrogen when R is alkyl and NR R R2 CN The compoundsaccording to formula (V) or (VIII),

repsectively, may be prepared by a wide variety of methods. The actualchoice between these methods in any particular instance dependsprimarily on the reactivity of the compound obtained, and the furtherprocessing to which it may be subjected to provide compounds such aspyrimidines of clinical utility, the further processing being itselfgoverned to a great extent by the nature of the amino group NR R thisacting as a leaving group in the further reactions.

Compounds according to formula (V) or (VIII) can be prepared by a methodprovided by the present invention, which comprises reacting thecorresponding benzaldehyde with the corresponding ,B-aminopropionitrilein the presence of a base in a polar aprotic solvent compatible with anddissolving both reactants.

Polar aprotic solvents suitable for the purpose includehexamethylphosphoramide and N,N dimethylacetamide, but best results havebeen obtained with dimethylsulphoxide as the solvent. Bases required forthe reaction include the hydroxide, the alkoxides, especially the loweralkoxides, preferably the methoxide or tert.-butoxide anions, and themethylsulphinyl carbanion, used in association with a suitable cation,such as an alkali metal (e.g. sodium or potassium) or a quaternaryammonium cation (e.g. N-benzyl-N,N,N-trimethylammonium).

Advantageously, the amount of base can be considerably reduced tocatalytic amounts, i.e. effective quantities of less than about 0.3molar equivalent calculated on the aldehyde used, particularly attemperatures above 60 C., preferably between C. and C. For instance,very good yields have been obtained in this manner usingdimethylsulphoxide as the solvent.

Very satisfactory yields have also been obtained for instance, with,B-primary aniline-substituted compounds with 0.5 to 2 molar equivalentsof the base at room (about 20 C.) or slightly elevated temperature up toabout 60 C. in the solvent. Dimethylsulphoxide may be replaced underthese conditions as well as by other polar aprotic solvents, especiallyhexamethylphosphoramide. It has been found most advantageous to uset-butoxide as the base in the form of the potassium salt indimethylsulphoxide for the preparation of B-anilinosubstituted compoundswhilst, for instance, the /3-morpholino-analogue may be preferred to beformed in the presence of sodium methoxide in the same medium.

Yet further methods provided by the present invention may be used toobtain selected or preferred ranges of compounds within the scope offormula (V) or (VIII). Accordingly, a method is provided for preparingsuch compounds, wherein the B-amino group NR R is a primary anilinogroup optionally substituted in the phenyl ring, as hereinbeforedefined, which comprises reacting the corresponding benzaldehyde withthe corresponding fi-primarypropionitrile. Preferably the reaction iscarried out in a polar non-aprotic solvent compatible with anddissolving the reactants in the presence of a base. Conveniently analkanol may be used for the purpose, and the reaction is desirablycarried out at elevated temperatures, say between 40 and 80 C. Thepreferred alkanol is methanol, particularly when the reactantbenzaldehyde is substituted with one or more methoxy groups, since it ispossible for exchange to take place between the solvent and thesubstituents. Bases already listed in relation to the other preparatorymethods are again applicable, and may, for instance, be used in aquantity molar equivalent calculated on the aldehyde, especially whenthe reaction is carried out at the lower end of the indicatedtemperature range.

Compounds according to formula (V) or (VIII) can also be prepared byreacting the corresponding fl-hydroxy- B-phenethylmethylsulphone orsulphoxide with the corresponding B-amino-propiontrile. Very preferablythe reactions carried out in the presenceof a base in a polarnon-aqueous solvent compatible with and dissolving both reactants ofelevated temperature above 30 C. The solvent may be an alkanol, such asmethanol, ethanol or isopropanol, or most conveniently a polar aproticsolvent such as exemplified above. The base is preferably sufficientlystrong on its own for a significant amount of the sulphone or sulphoxidereactant to be converted into the anionic form. Again hydroxides oralkoxides, preferably methoxide or t-butoxide, in the form of an alkalimetal salt, have been found very convenient for the purpose. The methodis especially suitable for making Type VIIIA.

Ths required 5 hydroxy-fi-phenethylenethylsulphone or sulphoxide for theabove method, may conveniently be provided by a process which comprisesthe steps of reacting an appropriately substituted benzoic acid esterwith dimethyl sulphone or dimethyl sulphoxide preferably in the presenceof a base, and selectively reducing the so obtained acetophenonemethylsulphone or methylsulphinyl derivative, for instance, with asuitable reducing agent e.g. borohydride or with aluminum isopropoxide.

The above defined group of fi-primary-anilinoot-benzylacrylonitriles canalso be prepared by a method which comprises reacting the correspondinganiline, generally in the form of an acid addition salt, with a compoundof the formula (V) or (VIII) carrying an amino substituent which has, asthe free amine HNR R a pKa value higher by at least about 3 to 4 unitsthan that of the aniline used for the reaction. For instance, amorpholino su'bstituent may, in this manner, be directly replaced by ananilino substituent, morpholine having a pKa value of about 8.6 and theaniline generally about 4 to 5. Preferably the reaction is carried in apolar nonaqueous solvent system, for instance, ethanol or glacial aceticacid, at reflux temperatures.

The compounds VIIIA are also preparable by reaction of PhNH withB-hydroxy-ut-benzylacrylonitriles:

X CH VIIIA This reaction is conveniently carried out in an organicsolvent such as benzene or a lower alcohol or without solvent and wherePh is as previously defined or PhNH could also be NR R where this is aspreviously defined.

The fl-hydroxy-ot-benzylacrylonitriles are prepared in exemplary fashionby acidification of a partly aqueous solution of a compound of typeVIIIB wherein R and R are not aromatic. For this variation in aqueousalcohol VIIIB is converted to the hydroxy compound X almostinstantaneously and in nearly quantitative yield.

The product may then be extracted with an organic solvent from theaqueous medium and reacted with a different amine to obtain a compoundaccording to formula (V) or (VIII). There is little or no tendency toisomerize to the benzal form during these manipulations.

Such a conversion from one amino derivative to another may be achievedin a very high yield, in many instances above 90% in both steps, and theproduct so obtained can be reacted to form other materials such asbenzylpyrimidines in a quality and yield often even better than thatprovided by using the original (Z-aminoderivative.

iIn addition, this method may be very advantageous for preparing certainfl-amino-a-benzylacrylonitriles, especially in cases where the NR Rgroup is basic but only weakly basic anilino group, eg p-chloro-anilino.In such instances, there are sometimes difficulties in preparing thecorresponding B-anilino-propionionitrile for reaction with thebenzaldehyde.

The B-hydroxy-a-benzylacrylonitriles may also be used as intermediatesfor further syntheses, and can, for instance, be alkylated to providethe appropriate ,B-alkoxya-benzylacrylonitrile, substantially free fromthe benzal isomer or acetal. The benzyl compound so formed and in suchpurity is also eminently suitable as a starting material for thesynthesis of benzylpyrimidines, and provides the latter in asubstantially increased yield and at a better quality than the mixtureof benzyl and benzal isomers, or the benzal isomer alone, of the methoddescribed in British Patent Specification No. 957,797.

Compounds according to formula (V) or (VIII), wherein the fi-amino groupNR R is a primary amino group other than anilino, or is a secondaryamino group, can also be prepared according to the present invention byreacting the corresponding B-alkoxy-a-benzylidenepropionitrile with anexcess of the appropriate amine in the presence of a base in an alkanol.Suitable bases are again those already listed for other methods.Preferably the base is the alkoxide corresponding to the solvent. Forinstance, a S-methoxide-a-benzylidenepropionitrile may be so convertedwith morpholine, in methanol containing sodium methoxide, to thecorresponding fl-morpholinoot-benzylacrylonitrile.

The above group of compounds according to formula (V) or (VIII), whereinthe fl-aminogroups NR R is other than the anilino group, can moreover beprepared according to the present invention by isomerising thecorresponding fl-amino-ot-benzylidene-propionitrile isomer with a basein a polar aprotic solvent. Under these conditions the benzal isisomerised into the benzyl form,

there appearing to be little or no benzal isomer after the process.Suitable aprotic polar solvents and bases are as hereinbefore describedwith reference to other reactions, and the most preferred solvent isagain dimethylsulphoxide and the most convenient bases are the methoxideand t-butoxide anions. Normally there is at least about 0.01, andpreferably about 0.1 molar concentration of base present in the solvent,and often not more than about 1 molar concentration, though as high as 2or even 4 molar concentrations may be used. The quantity of solvent isnot critical though there is preferably sufiicient throughout theisomerisation to dissolve the nitrile. The isomerisation can be effectedat room temperature but is most conveniently carried out in the presenceof heat, particularly good yields being obtained when it is carried outat a temperature above about 20 C. and up to about C. or even higher.The method has been very successfully applied toB-morpholinox-benzylidenepropionitriles, in particular to those having a3,4-dimethoxy or 3,4,S-trimethoxy-benzylidene group.

The starting benzal isomer, i.e., the appropriateamino-a-benzylidene-propionitrile, for the purposes of the abovereaction, can advantageously 'be prepared by reacting the correspondingbenzaldehyde with the corresponding B-amino-propionitrile in an alkanolin the presence of a catalytic amount of a base, in the sensehereinbefore used in the present specification, which means an effectivequantity of less than 0.3 molar equivalent calculated on the aldehydereagent.

Alkanols in this reaction are generally lower alkanols, having from 1 to4 carbon atoms, methanol being particularly preferred. Suitable basesare again those already suggested in connection with base catalysedcondensation reactions, but methoxides and tert.-butoxides, particularlythe former, are preferred for the present purpose. Best results may beobtained at elevated temperatures, and it is particularly preferred tocarry out the reaction at reflux temperatures.

As already indicated, the optimum route for preparing any particularcompound according to formula (V) or (VHI) may comprise a combination ofa number of the above processing possibilities, depending primarily onthe type of amino NR R group required. For instance, 3-primary-anilino-a-3',4',5-tri methoxy benzylacrylonitrile has certainespecial advantages as an intermediate for the preparation oftrimethoprim. Thus, the reaction of guanidine withfl-primary-anilino-a-benzylacrylonitriles generally proceeds appreciablyfaster than that with other 13- amino derivatives as defined by formula(V) or (VIII).

The fi-anilino-intermediate can moreover be produced readily without anybenzal isomer detectable by standard analytical methods, and can befurther processed to 2,4- diamino-S-benzylpyrimidines in a very highyield there being little or no polymer formation at all. It is mostnoteworthy that the reaction with guanidine is readily effected undermild conditions, and both the preparation of the intermediates and thefurther processing may be completed within hours rather than weeks.

Whilst B-primary-anilino-a-benzylacrylonitriles may be readily preparedby a wide variety of advantageous methods, the choice in any particularinstances depends partly upon the availability of the starting material,and, for instance, fi-anilino-propionitrile, when prepared from anilineand acrylonitrile, usually requires isolation and purification beforeuse. In contrast, the corresponding 18-morpholino-propionitrile can bereadily formed and need not be isolated. Furthermore, in cases oftrimethoxy-substituted benzyl derivatives, and base catalysed reactions,the cheaper and more widely available sodium methoxide is preferred formorpholino-derivatives, whilst the more expensive potassium t-butoxidegenerally gives best results for anilino-compounds. It may therefore onoccasion be advantageous to prepare the morpholino-intermediate firstand convert this into the corresponding anilino derivative to obtainoptimum results.

According to the present invention in a further aspect there is provideda method of preparing 2,4-diamino-- benzylpyrimidines as shown informula IX which are useful as antibacterials, wherein the benzyl groupcomprises an optionally substituted phenyl group, by reacting the corresponding fi-amino-a-benzylacrylonitrile of formula (V), substantiallyfree from contamination with the B-amino-abenZylidene-propionitrileisomer, as hereinbefore defined, with guanidine. In particular a methodis provided of preparing a compound of formula (IX) which comprisesreacting a compound of formula (VIII) substantially free fromcontamination with the [i-amino-abenzylidenepropionitrile isomer, ashereinbefore defined, with guanidine; in formula (IX) R R R and R are asdefined for formula (VIII). It has been found that the pyrimidineproducts are obtained in a satisfactorily high yield as well as withoutcontamination with polymers and coloured impurities. These aspects areof critical importance as indicated hereinbefore, since contemporaryrequirements for the purity of pharmaceutical products are verystringent and the products must be manufactured in a very pure form and,of course, at a reasonable cost. Both these necessities are now morereadily attainable, as a result of the present invention, for thebenzylpyrimidines.

To obtain S-benzylpyrimidines having particularly high activity, orpotentiating properties, the para position of the phenyl group ispreferably substituted with an alkoxy, i.e. methoxy group, especially incombination with a similar substitution at one or both adjacent metapositions. Such substitutions may also be present when at least one ofthe ortho-positions is occupied by a lower alkyl group, such as methyl.The pyrimidines are then trimethoprim, diaveridine, ormetoprim andanalogues thereof.

For the purposes of obtaining 5-benzylpyrimidines or in particular thoseof formula (IX) preferably having the above mentioned specificsubstituents, the appropriate 5- anilino-derivatives have been foundparticularly useful. Advantageously such an amine is reacted withguanidine, conveniently in a lower alcohol solvent, for example,methanol, ethanol, or isopropanol, at elevated temperatures. It isparticularly preferred that the reaction is carried out at the refluxtemperature of the reaction mixture, but useful routes are found attemperatures down to room temperatures. It has been found specificallythat the reaction takes place very readily, taking hours rather thanweeks for completion.

Although the reactivity with guanidine, or,B-amino-orbenzylacrylonitriles of formula (V) or (VIII), other thanthose having a fl-primary-anilino group, such as the morpholinoderivatives is lower, particularly in alkanols, it has been found thatthis can be increased and the yield substantially improved if theguanidine is employed in the form of the carbonate in a polar aproticsolvent, as hereinbefore described with reference to other methods, e.g.especially dimethylsulphoxide or hexamethylphosphoramide. Best resultshave been obtained in these particular cases with dimethylsulphoxide ator near 160 C. and, if the previous reaction step has been carried outin the same medium the fi-amino-a-benzylacrylonitrile intermediate neednot be isolated, although isolation is usually preferred since purerbenzylpyrimidine is obtained in this manner.

All. end products provided in the above manner have either antibacterialactivity or potentiating properties, al-

though the degree of such activity and potentiating effect may varyaccording to substitution and the purpose for which these compounds areemployed. Moreover, the products may themselves be used as startingmaterials to produce other derivatives and analogues by furtherreactions with functional groups thereon. Thusbenzyloxybenzyl-derivatives may, for instance, be converted into thecorresponding hydroxy-benzyl-derivatives by hydrogenation, or anyhydroxy-benzyl-derivatives alkylated to provide the requiredalkoxy-benzyl-substituted compounds.

According to the present invention, therefore, there are provided:

(i) N-substituted-[i-amino oz benzylacrylonitrile compounds according toformula (V), or, in particular, formula (VIII), substantially free fromcontamination with fi-amino-a-benzylidenepropionitrile, as hereinbeforedescribed;

(ii) the various methods of preparing fi-amino-m-benzylacrylonitriles offormula (V) or (VIII), as hereinbefore described;

(iii) the various methods of converting such aB-aminou-benzylacrylonitrile into a different compound of the same classwith respect of the fl-amino-substitution, as hereinbefore described;

(iv) N-substituted B-amino-wbenzylacrylonitriles whenever prepared by amethod defined under either of paragraphs (ii) and (iii), ashereinbefore described;

(v) ,e-hydroxy-u-benzylacrylonitriles substantially free fromcontamination with isomers, as hereinbefore described;

(vi) the methods of preparing the compounds defined under paragraph (v);

(vii) the methods of preparing i-benzylpyrimidines by using compounds orproducts of methods, according to any one of paragraphs (i) to (vi), ashereinbefore described:

(viii) S-benzylpyrimides whenever prepared by a method including stepsaccording to any one of paragraphs (ii), (iii), (vi) and (vii).

The present invention, in each of the above aspects, is particularlypreferred when the phenyl group is a 3,4-dimethoxy, 3,4,5-trimethoxy or2-methyl 4,5 dimethoxy group, since there are then produced theespecially valuable compounds diaveridine, trimethoprim or ormetoprim,or the respective intermediates therefor.

The following Examples illustrate the invention:

EXAMPLES Example 1 3,4,-S-Trimethoxybenzaldehyde (98 g.), 18anilinopropionitrile g.), and dimethylsulfoxide (175 ml.) were heatedtogether to 125 C. A solution of sodium methylate (5 g.) in methanol (50ml.) was gradually added and in so doing the reaction temperature roseto 130 C., and this temperature was maintained for a further 17 minutes.The reaction mixture was chilled; Water was added to a persistent haze;seeds of fi-anilino-a-Za,4,5 -trimethoxybenzylacrylonitrile were added;and the mixture was stirred at 25 C. until precipitation was copious.Additional water (400 ml.) was added, and the product was collected byfiltration and reslurried in ice water (60 ml.). The collection andreslurry procedures were repeated using cold (-5 C.) denatured alcohol(320 ml.), and the crystallineB-anilino-m-3,4,5-trimethoxybenzylacrylonitrile was finally collected;washed with cold denatured alcohol (40 ml.), and hexane ml.). Wt.= g.(71%; 98% pure lby U.V. assay) m.p. 132-133 C. (recrystallised frommethanol).

Example 2 3,4,5 trimethoxybenzaldehyde (49 g.), ,6 anilinopropionitrile(40 g.), and dimethylsulfoxide (85 ml.) were heated together to C., anda solution of potassium hydroxide (2.5 g.) in methanol (12.5 ml.) wasadded over a 35 min. period. The temperature of the reaction wasmaintained at 130135 C. for an additional 30 min., and the reactionmixture was then treated as in Example 1 to give 5 anilino 0c 3,4,5trimethoxybenzylacrylonitrile as a crystalline solid. Wt.=57 g. (70% 1 1Example 3 3,4,5 Trimethoxybenzaldehyde (117.5 g.; 0.6 mole), ,8anilinopropionitrile (101 g.; 0.69 mole), and dry distilleddimethylsulfoxide (348 ml.) was heated together to 40 C. until solutionwas complete. The mixture was chilled to 12 C. and a solution ofpotassium t-butoxide in t-butanol (13.6%; 491 'ml.; 0.6 mole) was addedover the course of about min., such that the final temperature was aboutC. The temperature was raised to C. and maintained for one hour.t-Butanol was then stripped from the reaction using vacuum to a finalpot temperature of C. The residue was chilled to 30 C. and water (100ml.) and denatured ethanol (50 ml.) added. The mixture was seeded andafter obvious crystallisation more ice/water (500 ml.) and denaturedethanol ml.) were added. When the final temperature of the mixture was510 C. the crystalline ,8-anilino-e-3,4,5- trimethoxybenzylacrylonitrilewas collected and washed with a mixture of cold water/denatured ethanol(:15; 600 ml.). Wt.=l8l.7 g. (94% pure by UV. assay; yield 88 Example 43,4 Dimethoxybenzaldehyde (88 g.), 5 anilinopropionitrile (82.5 g.),dimethylsulfoxide (160 ml.), and sodium methylate were heated togetherat C. for 2 /2 hr. The reaction mixture was then chilled at 25 C. anddiluted with isopropyl alcohol (40 ml.) and Water. When crystallisationwas obvious further water (200 ml.) was added. The mixture was cooled to5 C. and crystalline ,B-anilino or 3,4 dimethoxybenzylacrylonitrile wascollected and washed with cold water/isopropyl alcohol (1:1). Wt.=99 g.(61%) mp. 153154 C. (recrystallised from denatured alcohol).

Example 5 Piperonaldehyde (45 g.), fi-anilinopropionitrile (52 g.) anddimethylsulfoxide (96 ml.) were heated together to 120 C. and a solutionof sodium methylate (2.5 g.) in methanol (12 ml.) was added over a 5min. period. The temperature was maintained at 115120 C. for 1 hr. andthe mixture was then poured into ice-water. The resulting gum wascollected by decantation and was likewise washed with water (2x100 ml.).Methanol ml.) was then added and the mixture was heated until solutionwas complete. Cooling to 5 C. gave B-anilino-apiperonylacrylonitrile asa crystalline solid which was collected, and washed with cold methanol,ether, and pentane. Wt.=45 g.) m.p. 150.5-151 C. (recrystallised frommethanol).

Example 521 The procedure of Example 3 was repeated using3,4-dimethoxy-S-bromobenzaldehyde (78 g.) and gave danilino oc 3,4dimethoxy-S-bromobenzylacrylonitrile. Wt.=62 g. (52%) mp. 151154 C.

Example 6 Sodium methylate (5.4 g.) in t-butanol (50 ml.) was slowlytreated with a solution of 3,4,5-trimethoxybenzaldehyde (20 g.) andfl-(p-methylanilino)-propionitrile (17.5 g.) in dimethylsulfoxide (50ml.). The mixture was stirred at 45 C. for one hour and the alcohol thenremoved in vacuo (bath temperature j 50 C.). The mixture was poured intoice-water and the crude product collected and recrystallised frommethanol to give B-(pmethylanilino) 0c 3,4,5trimethoxybenzylacrylonitrile. Wt.=30 g. (89%) m.p. ISO-151 C.(recrystallized from methanol).

Example 7 The procedure of Example 6 was repeated using,B-(pchloroanilino) propionitrile (20 g.) in place offl-(pmethylanilino) propionitrile. Wt. of recrystallisedfl-(pchloroanilino) a 3,4,5 trimethoxybenzylacrylonitrile=24 g. (67%)mp. 172173 C. (recrystallised from methanol).

12 Example 8 The procedure of Example 6 was repeated usingfl-(pmethoxyanilino) propionitrile (19.5 g.) in place offi-(pmethylanilino) propionitrile. Wt. of recrystallisedfl-(pmethohxyanilino) a 3,4,5 trimethoxybenzylacrylonitrile=11 g. (33%)mp. 125125 C. (recrystallised from methanol).

Example 9 2-Methyl-4,S-dimethoxybenzaldehyde (18 g.), dimethylsulphoxide(35 ml.), sodium methoxide (1.0 g.), and p anilinopropionitrile wereheated together at 95 C. for 1 /2 hr. The mixture was then poured intoice-water (150 g.), and the resulting solid collected by decantation.The crude product was recrystallised from methanol (100 ml.) and theresulting fl-anilino-u-(2-methyl-4,5-dimethoxybenzyl) acrylonitrile wascollected, and washed with methanol and hexane. Wt.=l9 g. (60%) mp.1171l9 C. (recrystallised from ethanol/methanol).

Example 10 p-Benzyloxybenzaldehyde (25 g.), ,B-anilinopropionitrile (22g.), and dimethylsulphoxide (25 ml.) were heated together to 95 C., anda slurry of sodium methoxide (1 g.) in dimethylsulphoxide (20 ml.) wascarefully added such that the temperature rose to C. The mix ture washeated to 125-130 and held at that temperature for 1 /2 hr. The reactionmixture was poured into icewater (500 ml.), and the resulting solid wascollected and washed by decantation. The crude product was slurried incold ethanol to give fi-anilino-a-(p-benzyloxybenzyl) acrylonitrile.Wt.=27 g.

Example 11 fi-Morpholinopropionitrile (47 g.), sodium methoxide (2 g.),and dimethylsulphoxide (40 ml.) were heated together to 65 C., and asolution of 3,4,5-trimethoxybenzaldehyde (50 g.) in dimethylsulphoxide(40 ml.) was added slowly such that the temperature rose to 7075 C.After 3 min. at this temperature the mixture was cooled to 30 C., andisopropyl alcohol (30 ml.) and water suflicient to create a persistenthaze were added. The mixture was seeded and, after crystallisation wasobvious, water (80 ml.) was added. Crystallinefl-morpholino-m3,4,5-trirnethoxybenzylacrylonitrile was collected andwashed with isopropyl alcohol (50 ml.). Wt.=73.5 g. (89%) mp. 115ll7 C.(recrystallised from methanol).

Example 12 3,4,5-Trimethoxybenzaldehyde (20 g.),,B-N-methylanilinopropionitrile (18 g.), dimethylsulphoxide (40 ml.),and sodium methoxide (1 g.) were heated together at 115 C. for 1.5 hr.The mixture was poured into icewater (800 ml.) and the crude productwhich precipitated gave crystalline ,8-N-methylanilino-u-3,4,5-trimethoxybenzylacrylonitrile after a slurry in methanol (50 ml.).Wt.=17 g. (50%) mp. 121-122 C. (recrystallised from methanol).

Example 13 3,4,5-Trimethoxybenzaldehyde (50 g.),B-piperidinopropionitrile (40 g.), dimethylsulphoxide (60 ml.), andsodium methoxide (2 g.) were reacted together at 75 C. for 20 min. andon work-up gave ,8-piperidino-ot-3,4,5- trimethoxybenzylacrylonitrile.Wt.=40 g. (50%) rn.p. 9293 C. (recrystallised from methanol).

Example 14 3,4,S-Trimethoxybenzaldehyde (25 g.),B-pyrrolidinopropionitrile (20 g.), dimethylsulphoxide (25 ml.) andsodium methoxide (1 g.) were reacted together at 75 C. for 10 min., andon work-up gave fi-pyrrolidino-a-3,4,5- trimethoxybenzylacrylonitrile.(Wt.:28 g. (75%) mp. 123124 C. (recrystallised from methanol).

Example 15 3,4,5-Trimethoxybenzaldehyde g.),B-N-dimethylaminopropionitrile (16 g.), dimethylsulphoxide ml.), andsodium methoxide (1 g.) were reacted together at 70 C. for 10 min., andon work-up gave fi-dimethylamino on 3,4,S-trimethoxybenzylacrylonitrile.Wt.=25 g. (73%) m.p. 122123 C. (recrystallised from methanol).

Example 16 3,4,S-Trimethoxybenzaldehyde g.), fi-benzylaminopropionitrile(45 g.), dimethylsulphoxide (80 ml.), and sodium methoxide (2 g.) wereheated together at 100 C. for 2 hr., and on work-up gavefi-benzylamino-a-3,4,5- trimethoxybenzylacrylonitrile. Wt.=32 g. (37%)m.p. 130.5131 C. (recrystallised from methanol).

Example 17 3,4,S-Trimethoxybenzaldehyde (25 g.), fl-morpholinmpropionitrile (20 g.), sodium methoxide (2' g.), and N,N-dimethylacetamide (25 ml.) were reacted together at 90 95 C. for 1 /2hr., and on work-up gave B-morpholinou-3,4,S-trimethoxybenzylacrylonitrile. Wt.=l5 g. (37%).

Example 18 fl-Morpholinopropionitrile (40 g.), dimethylsulphoxide (40ml.), and sodium methoxide (2 g.) were heated together at C. and asolution of 3,4-dimethoxybenz aldehyde (44 g.) in dimethylsulphoxide (40ml.) was added. The reaction was held at -80 C. for 15 min., and thenworked-up as in Example 11 to give crystalline 3 morpholino a. 3,4dimethoxybenzylacrylonitrile. Wt.=4l g. (57%) m.p. 130131 C.(recrystallised from methanol).

Example 19 The procedure of Example 18 was repeated usingp-dimethylaminopropionitrile (28 g.) in place ofSi-morpholinopropionitrile, and on work-up gave,B-dimethylaminoa-3,4-dimethoxybenzylacrylonitrile. Wt.=31 g. (50%) m.p.85-86 C. (recrystallised from methanol).

Example 20 fl-Morpholinopropionitrile (20 g.), dimethylsulphoxide (30ml.), and sodium methoxide (1 g.) were heated together at C. and asolution of piperonaldehyde (19 g.) in dimethylsulphoxide was added. Themixture was reacted at 80 C. for 15 min., and on work-up gaveB-morpholino-a-piperonylacrylonitrile. Wt.=21 g. (61%) m.p. 85.5 C.(recrystallised from methanol).

Example 21 The procedure of Example 20 was repeated using 3,4-dimethoxy-5-bromobenzaldehyde (31 g.) in place of piperonaldehyde and onwork-up gave fi-morpholino-a-3,4- dimethoxy-5-bromobenzylacrylonitrile.Wt.=28 g. (60%) m.p. 94.595 C. (recrystallised from denatured ethanol).

Example 22 Example 24 8 Hydroxy [5' 3,4,5trimethoxyphenethylmethylsulphone (29 g.), p-anilinopropionitrile (16.5g.), and dimethylsulphoxide (40 ml.) were heated together to 40 C., anda solution of potassium-t-butoxide in t-butanol (13.6%; 83 ml.) wascarefully added. The temperature was maintained at 45 C. for 1 hr.Alcohol was then removed from the reaction mixture by vacuum evaporationand the residue was poured into ice-water (200 ml.) The crudecrystalline product was collected and recrystallised from ethanol togive 5 an'ilino-a-3,4,5-trimethoxybenzylacrylonitrile. Wt.=26 g. (afterWashing with ethanol and hexane; 80%).

Example 25 The procedure of Example 2 4 was repeated usinghexamethylphosphoramide (40 ml.) in place of dimethylsulphoxide, and onWorkaup 8-anilino-a-3, 4,5-t1imethoxybenzylacrylonitrile was obtained.Wt.'=26 g. (80%) m.p. 126128 C.

Example 26 ,8 Hydroxy fl-3,4,5 trimethoxyphenethylmethylsulphone (5 g.),fl-anilinopropionitrile (3 g.), dimethylsulphoxide (20 ml.), and asolution of potassium hydroxide in methanol (20%; 2 ml.) were reactedtogether at C. for 20 min. Work-up gaveB-aniIinO-a-B,4,5-trimethoxybenzyl-acrylonitrile (3 g.; 53%). m.p..126-129 C. (recrystallised from ethanol).

Example 27 The procedure of Example 26 was repeated usinghexamethylphosphoramide (20 ml.) in place of dimethylsulphoxide and onwork-up ga've fl-anilino-a-3,4,5-tri methoxy'benzylacrylonitrile (2 g.;36%) m.p. -127 C. (recrystallized from ethanol).

Example 28 The procedure of Example 26 was repeated using sodiummethoxide (0.5 g.) in place of potassium hydroxide in methanol, and onwork-up gave B-anilino-a-3,4,5-trimethoxybenzylacrylonitrile. Wt=3 g.(54%) m.p. 128- C.

Example 29' B Hydroxy [3 3,4,5 trimethoxyphenethylmethylsulphone (10g.), p-anilinopropionitrile (5.1 g.), hexamethylphosphoramide (20 ml.),and sodium methoxide (1 g.) were reacted together at 60 C. for 30 min.,and on work-up gave )8-anilino-a-3,4,5-trimethoxybenzylacrylonitrile.Wt.=6 g. (54%) m.p. 127-129 C.

Example 30 The procedure of Example 28 was repeated using N,N-dimethylacetamide (25 ml.) in place of dimethylsulphoxide, and onwork-up gave fi-aniline-a-3,4,5-trimethoxybenzylacrylonitrile. Wt.=2.5g. (45%) m.p. 125-128 C.

Example 31 fi-Hydroxy p 3,4,5atrimethoxyphenethylmethylsulphoxide (5.4g.), B anilinopropionitrile (3 g.), dimethylsulphoxide (25 ml.), andsodium methylate (0.5 g.) were reacted together at 9095 C. for 1 hr. Themixture was then poured into ice-water: the solid collected andrecrystallised from denatured ethanol to give ,B-anilino-a-3,4,S-trimethoxybenzylacrylonitrile. Wt.=2 g. (30%) m.p. 125-127 C.

Example 32 The procedure in "Example 31 was repeated using potassiumhydroxide (2 g.) in methanol (5 ml.) in place of sodium methoxide, andon work up gave fi-al11li1'10-oc-3,4,5- trimethoxybenzylacrylonitrile.Wt.=2 g. (30%) Imp. 125- 128 C.

'Example 33 The procedure in Example 31 was repeated usinghexamethylphosphoramide in place of dimethylsulphoxide and sodiummethyl-ate (2 g.), and on work-up gave,B-anilinoot-3,4,S-trimethoxybenzylacrylonitrile. Wt.=2 g. (30%) m.p.125429 c.

1 5 Example 34 The procedure in Examlple 31 was repeated usingpotassium-t-butoxide in t-butanol (13.6%; ml.) in place of sodiummethoxide, and on Work-up gave fi-anilino-a- 3,4,5trimethoxybenzylacrylonitrile. Wt.=1 g. (15%) m.p. 128130 C.

Example 35 The procedure in Example 34 was repeated usinghexamethylphosphoramide (25 ml.) in place of dimethylsulphoxide, and onwor k-up gave fi-anilino-a-3,4,5-trimethoxybenzylacrylonitrile. Wt.':1g. (15 m.p. 123-12 6 C.

Example 36 13 Morpholinopropionitrile (3.0 g.), ,B-hydroxy Si-3,4,5-trimethoxyphenethylmethylsulphone (2.9 g.), sodium methoxide (0.3 g.)and hexamethylphosphoramide (6 ml.) were reacted together at 60-65 C.for min., and then poured into ice-Water (5 0 ml.). The crude solid wascollected by decantation and recrystallised from ethanol (10 ml.) togive fi-morpholino -u-3,4,S-trimethoxybenzylacrylonitrile. W 1:2 g.(-60% Example 37 The procedure in Example 36 was repeated usingbenzyltrimethylammonium hydroxide in place of sodium methoxide and onwork-up fi-morpholino-a-3,4,5-trimeth oxy benzylacrylonitrile wasobtained in yield.

Example 38 3,4 Dimethoxybenzaldehyde (41.5 g.), p-anilinopropionitrile(38.5 g.), sodium methoxide (40 g.) and methanol (200 ml.) were reactedunder reflux for 3 hr. The solvent was then removed by evaporation invacuo and the resulting paste was recrystallised from methanol to give,8 anilino a-3,4,dimethoxybenzylacrylonitrile. Wt.= g. (75%) m.p.153-154 C. (recrystallised from ethanol).

Example 40 B-Morpholino-a 3,4,5 trimethoxybenzylacrylonitrile (318 g.),aniline (107 g.) and glacial acetic acid (69 g.) Were heated together at95 C. for 45 min. Isopropanol (300 ml.) was then added and the mixturewas cooled to 30 C.; seeded; and treated with water (300 ml.) aftercrystallisation was obvious. Filtration gave fi-anilino-a-3,4,5-trimethoxybenzylacrylonitrile. Wt.=296 g. (after washing with waterand isopropanol; 91%

Example 41 Aniline hydrochloride, from aniline (10 g.) and conc.hydrochloric acid (12 ml. andfl-morpholino-a-3,4,5-trimethoxybenzylacrylonitrile (30 g.) were reactedtogether in refluxing isopropanol (50 ml.) for 15 min. Water (25 ml.)was added and on cooling crystals of {3-anilinoa 3,4,5trimethoxybenzylacrylonitrile were obtained. Wt.=29 g.

Example 42 B-Methoxy-a-3,4,5 trimethoxybenzylidenepropionitrile (53 g.),obtained according to method described in B.P. 957,797, morpholine (100ml.), sodium methoxide (14 g.), and methanol (53 ml.) were heatedtogether at 90 C. for 15 min. The solvent was removed by evaporation invacuo and the residue was poured into ice-Water. The thick oil whichseparated was collected and washed by decantation and on treatment withether gave crystalline ,s-morpholino-u 3,4,5trirnethoxybenzylacrylonitrile. Wt.=53 g. (88%).

Example 43 3,4,5 Trimethoxybenzaldehyde (25 g.),fi-morpholinopropionitrile' (20 g.), methanol (50 ml.), and sodiummethoxide (1 g.) were heated together under reflux for 72 hrs. SolventWas then removed in vacuo and the residue was crystallised fromdiethylether ml.) to givefi-morpholino-a-3,4,5-trimethoxybenzylidenepropionitrile. Wt. 18 g.(44%) m.p. 100.5-102 C. (recrystallised from methanol).

Example 44 3,4 Dimethoxybenzaldehyde (21 g.), B-morpholinopropionitrile(22 g.), sodium methylate (1 g.) and methanol (50 ml.) were heatedtogether under reflux for 20 hr. Work-up as in Example 43 gave5-morpholino-u-3,4 dimethoxybenzylidenepropionitrile. Wt.=25 g. (67%)m.p. 9597 C. (recrystallised from methanol).

Example 45 The procedure of Example 43 using fi-piperidinopropionitrile(20 g.) gave B-piperidino-a-3,4,5-trimethoxybenzylidenepropionitrile.Wt.=32 g. (79%) m.p. 6062 C. (recrystallised from isopropanol).

Example 46 The procedure of Example 43 using B-pyrrolidinopropionitrile(20 g.) gave ,B-pyrrolidino-a-3,4,5-tri.methoxy benzylidenepropionitrileas an oil. Wt.'=37 g. (96%).

Example 47 The procedure of Example 43 usingfi-dimethylaminopropionitrile (18 g.) gavefl-dimethylamindtx-3,4,5-trimethoxybenzylidenepropionitrile. Wt.=20 g.(57%) m.p. 81-83" C. (recrystallised from methanol).

Example 48 Piperonaldehyde (30 g.), ,B-morpholinopropionitrile (40 g.),methanol (75 ml.) and sodium methylate (1.5 g.) were heated togetherunder reflux for 20 hr. Solvent was removed in vacuo and the residuerecrystallised from ether, after treatment with aqueous sodiumbisulphite, to give fi-morpholino-u-piperonylidenepropionitrile. Wt.=29g. (53%) m.p. 80-85 C. (recrystallised from methanol).

Example 49 fi-Morpho1ino-a-3,4,5 trimethoxybenzylidenepropionitrile (3g.), dimethylsulphoxide (10 m1.) and sodium methoxide (0.1 g.) wereheated together at 50-60 C. for 10 min. Work-up gave crystallineB-m0rpholino-m-3,4, S-trimethoxybenzylacrylonitrile. m.p. -117 C.

Example 50 The procedure of Example 49 was repeated using ,8-dimethylamino-a 3,4,5 trimethoxybenzylidenepropionitrile (4 g.) and onwork-up gave ,8-dimethylamino-a-3A, 5-trimethoxybenzylacrylonitrile.Wt.=3.2 g. (80%) m.p. 1l9-122 C. (recrystallised from methanol).

Example 51 The procedure of Example 49 was repeated using 5-piperidino-a 3,4,5 trimethoxybenzylidenepropionitrile (3.5 g.) and inwork-up gave B-piperidino-a-3,4,5-trimethoxybenzylacrylonitrile. Wt.=2.7 g. (77%) m.p. 89- 92 C.

Example 52 B-Dimethylamino-a 3,4,5 trimethoxybenzylidenepropionitrile (2g.), hexamethylphosphoramide 10 ml.), and sodium methoxide (0.05 g.)were heated together at 30 C. Conversion to8-dimethylamino-u-3,4,5-trimethoxybenzylacrylonitrile was complete in 1min. and this compound was obtained on work-up. Wt.=l g. (50%) m.p.118-120 C. (recrystallised from methanol).

1 7 Example 53 fi-Dimethylamino-ot-3,4,5trimethoxybenzylidenepropionitrile (2g), dimethylsulphoxide (10 ml.) andpotassium-t-butoxide (0.05 g.) at 30 for 1 min. gave E dimethylamino-nt3,4,5 trimethoxybenzylacrylonitrile. Wt.=1 g. (50%) m.p. 119121 C.

Example 54 fiDimethylamino-a-3,4,5 trimethoxybenzylidenepropionitrile (4g.), hexamethylphosphoramide (10 ml.), and potassium-t-butoxide (0.05g.) at 30 C. for 1-2 min. gave fl-dimethylamino'a-3,4,5trimethoxybenzylacrylonitrile. Wt.=3 g. (75%) m.p. 117--119 C.

Example 55 B-Dimethylamino a 3,4,S-trimethoxybenzylidenepropionitrile (2g.), dimethylsulphoxide (10 ml.), and 3 drops of a saturated solution ofpotassium hydroxide in methanol at 40 C. for 5 min. gave,B-dimethylamino-a- 3,4,5-trimethoxybenzylacrylonitrile Wt.=1.3 g. (65%)m.p. 118120 C.

Example 56 The procedure as in Example 55 using hexamethylphosphoramidein place of dimethylsulphoxide in 2 min. gave fl-dimethylamino-a-3,4,5trimethoxybenzylacrylonitrile. Wt.:1.8 g. (90%) m.p. 121-123 C.

Example 57 The procedure as in Example 49 using fi-pyrrolidino-w 3,4,5trimethoxybenzylidenepropionitrile gave ,B-pyrrolidime-3,4,5trimethoxybenzylacrylonitrile. m.p. 123- 124 C.

Example 58 The procedure as in Example 52 using B-morpholino-a-3,4,S-dimethoxybenzylidene propionitrile gavefl-morpholino-a6,4-dimethoxyacrylonitrile. 127129 C.

Example 59 The procedure as in Example 49 usingp-morpholinoa-piperonylidenepropionitrile (5.0 g.) gavefl-morpholinou-piperonylacrylonitrile. Wt.=4.5 g. (90%) m.p. 82- 84 C.

Example 60 The procedure as in Example 50 using N,N-dimethylacetamide inplace of dimethylsulphoxide gave fi-dimethylamino-u-3,4,5trimethoxybenzylacrylonitrile in 83% yield. m.p. 121-123 C.

Example 61 The procedure as in Example 52 using benzyltrimethylammoniumhydroxide in place of sodium methoxide gave p-dimethylamino-a-3,4,5trimethoxybenzylacrylonitrile in 86% yield. m.p. 122l23 C.

Example 62 B-Morpholino-ot-3,4,5 trimethoxybenzylacrylonitrile (157 g.)was treated with cone. hydrochloric acid (73 ml.) in water (180 ml.) at60 C. for min. The reaction mixture was cooled, extracted withchloroform (100 ml.; 75 ml.; 75 ml.), and the extracts were back- Washedwith Water (75 ml.). Removal of solvent gave,B-hydroxy-a-3,4,5-triinethoxybenzylacrylonitrile as a thick oil.Wt.=125 g. (theory).

Example 63 fl-Hydroxy-a-3,4,5 trimethoxybenzylacrylonitrile (70 g.) inmethanol (150 ml.) at 10 C. was treated with dimethylsulphate (39 g.).To the mixture was then gradually added a solution of potassiumhydroxide g.) in methanol ml.) and water (12 ml.) and the reaction wasthen kept at 10 C. for 15 min. The mixture was next heated to 60 C. for15 min.; then cooled; and finally solvent was removed to a residue whichwas slurried in water 100 ml.) and extracted into chloroform (2X ml.).The chloroform extract, after back-washing with water (70 ml.), drying,and treatment with charcoal, was evaporated to dryness to giveflanethoxy-a-3,4,5-trimethoxybenzylacrylonitrile. Wt.=61 g. (80%).

Example 64 Example 65 The product from Example 6 was convertedto2,4-diarnino 5 (3,4,5'-trimethoxybenzyl)pyrimidine by the procedure ofExample 64 in 2 hr. Yie1d=90% Example 66 The product from Example 7 wasconverted to 2,4-diamino 5 (3,4',5-trimethoxybenzyl)pyrimidine by theprocedure of Example 64 in 2 hr. Yield=%.

Example 67 The product from Example 8 was converted to 2,4-diamino 5(3',4,5'-trimethoxybenzyl)pyrimidine by the procedure of Example 64 in 4/2 hr. Yield=90%.

Example 68 The procedure of Example 64 was repeated using anilino-a-3,4dimethoxybenzylacrylonitrile (29.4 g.) and gave 2,4-diamino-5-(3,4dimethoxybenzyl)pyrimidine. Wt.=25.5 g. (98%) m.p. 230233 C.

Example 69 The procedure of Example 64 was repeated using Banilino-a-piperonylacrylonitrile (28 g.) and gave2,4-diamino-S-piperonylpyrimidine. Wt.=22 g. (89.5%) m.p. 252253 C.(recrystallised from denatured alcohol).

Example 70 The procedure of Example 64 was repeated using B-anilino-a-2-methyl 4,5-dimethoxybenzylacrylonitrile (16 g.) and after18-20 hr. reflux gave 2,4 diamino-5-(2-methyl-4,5'-dimethoxybenzyl)pyrimidine. Wt.=11.5 g. (92%) m.p. 230-231C.

Example 71 The procedure of Example 64 Was repeated using,B-anilino-tx-3,4-dimethoxy 5 bromobenzylacrylonitrile (62 g.) and gave2,4diamino 5 (3,-4-dimethoxy-5-bromo benzyl)pyrimidine. Wt.=38 g. (70%)m.p. 203.5205 C.

Example 72 The procedure of Example 64 was repeated using flanilino a pbenzyloxybenzylacrylonitrile (25 g.) and gave after 4 hr. reflux2,4-diamino-5-(p-benzyloxybenzyl) pyrimidine. Wt.=20.5 g. This wasconverted to its acetate salt by treatment with acetic acid. Wt.=15 g.

Example 73 2,4 Diamino 5 (p-benzyloxybenzyl)pyrimidine acetate (4.6 g.)in methanol (200 ml.) was hydrogenated at low pressure over 5%Palladium/Carbon. The filtrate after removal of catalyst was evaporatedand the resulting residue purified by dissolution in hot dilute aceticacid and re-precipitation with ammonium hydroxide to pH 9. Crystalline2,4-diamino 5 (p hydroxybenzyl)pyrimi- .19 dine was collected and Washedwith water. Wt.=2.16 g. m.p. 300303 C.

Example 74 ,8-Monpholino a 3,4,5-trimetihoxybenzylacrylonitrile (32 g.),guanidine carbonate (34 g.) and dimethylsulphoxide (50 ml.) were heatedtogether at 160 C. for 1 hr. with good stirring. The reaction mixturewas cooled and poured into ice-water (200 ml.) and gave 2,4-diamino-5-(3',4,5 trimethoxybenzyDpyrim-idine which was collected and washed withwater and acetone. Wt.=23.6 g.

Example 75 The procedure of Example 74 was repeated using ,B-pyrrolidinoc 3,4,5 trimethoxybenzylacrylonitrile and gave 2,4-diarnino 5 (3',4',5'trimethoxybenzyl)pyrimi dine.

Example 78 The procedure of Example 74 was repeated usingfi-dimethylarnino a 3,4,5-trimethoxybenzylacrylonitrile and gave 2,4diamino 5 (3,4,5-trimethoxybenzyl)pyrimidine.

Example 79 The procedure of Example 74 was repeated using [-3-benzylamino 0c 3,4,S-trimethoxybenzylacrylonitrile and gave 2,4 diamino5 (3,4',5'-trimethoxybenZyDpyrimidine.

Example 80 The procedure of Example 74 was repeated using 18- morpholinoa 3,4 dimethoxybenzylacrylonitrile and gave 2,4diamino-S-(3',4'-dimethoxybenzyl)pyrimidine.

Example 81 The procedure of Example 74 was repeated using ,8-dimethylamino u 3,4 dimethoxybenzylacrylonitrile and gave 2,4diamino-S-(3,4'-dimethoxybenzyl)pyrimidine.

Example 82 The procedure of Example 74 was repeated using [3- morpholinoa piperonylacrylonitrile and give 2,4-piperonylpyrimidine.

Example 83 The procedure of Example 74 was repeated using ,8- morpholinoor 3,4 dimethoxy-S-bromobenzylacry1onitrile and gave 2,4-diamino 5(3,4'-dimethoxy-5-bromObenZyDpyrimidine.

Example 84 The procedure of Example 64 was repeated using 8- rnethoxy a3,4,5-trimetl1oxybenzylacrylonitrile (54 g.) and after 20 hr. refluxgave 2,4 diamino 5 (3',4',5'-trirmBthoxybenzyDpyrimidine. Wt.=56 g.(94%) m.p. 198- 20 C.

Example 85 Under the conditions of Example 24 the S-hydroxy-B- (3,4dichlorophenethylmethylsulfone, B-hydroxy-fiw, meta,p-iodophenybmethylstflfones and fl-hydroxy-p-(abromophenethylsulfones)were condensed with B-anilinopropionitrile to yield the corresponding 8anilino uhalogenobenzylacrylonitriles,

Example 86 The procedure of Example 64 was repeated using the productsof Example to give 2,4-Diamino-5-(3',4'-dichlorobenzyl)pyrimidine, m.p.237-239, 2,4-Diamino-5- (0-iodobenzyl)pyrimidine, m.p. 265-267,2,4-Diamiuo-5- (m iodobenzyDpyrimidine, m.p. 220.5-222, 2,4-Diamino 5 (piodobenZyDpyrimidine, m.p. 246-248, and 2,4 diamino-S-(obromobenzyl)pyrimidine, m.p. 248250.

Example 87 fl-hydroxy a 3,4,S-trimethoxy-benzylacrylonitrile 25 grams,denatured ethanol (70 ml.) 2,4-dimethyl aniline (14 m1.) refluxedtogether for 1 hr. Solvent removed by evaporation and vacuum and theresidue was poured into ice water. The resulting thick gum was collectedand recrystallized from methanol to give crystalline/8-,2,4-dimethylanidino-a-3,4,5-trimethoxybenzylacrylonitrile. Wt. :11g. (31% yield) M.P. l23l25 C.

Example 88 Procedure of Example 87 was repeated using3,4,5-trimethoxyaniline and gave fi-3,4,S-trimethoxybenzylacrylonitrilein 65% yield. M.P. 156161 C. Recrystallized from denatured ethanol.

Example 89 Procedure of Example 87 was repeated using2,5-dichloroaniline and gavefl-Z,5-dichloroanilino-a-3,4,5-trimethoxybenzylacrylonitrile. 20 g., 51%yield. A sample recrystallized from denatured ethanol melted at 130 C.,resolidified, and then remelted at 150 C.

Example 90 Procedure of Example 87 was repeated using a-naphthylamine14.3 gr. and gave crystallinep-l-naphthylamino-a6,4,S-trimethoxybenzylacrylonitrile. Wt.=26 gr. 70%yield, m.p. 107-109 C.

Example 91 The product from Example 87 was converted to trimethoprim bythe procedure of Example 64 in 4 hrs. Yield 92%.

Example 92 The product from Example 88 was converted to trimethoprim bythe procedure of Example 64 in 3 hrs. Yield above 90%.

Example 93 The product from Example 89 was converted to trimethoprim bythe procedure of Example 64 in 1.5 hrs. Yield This reaction was repeatedas in Example 64 except at room temperature and useful yield oftrimethoprim was obtained in several hrs.

Example 94 The product from Example 90 was converted to tr-imethoprim bythe procedure of Example 64 in several hrs. Yield 72%.

Example 95 Methyla-(3,4,S-trimethoxyacetophenone) Sulphone H2 2 H-CO-SCH3 Charge into a 500 ml. three necked flask equipped with stirrerand reflux condenser, 27 gms. (0.69M) sodium amide, 225 m1.dimethylsulphoxide and 56.5 gm. dimethylsulphone (0.6M). Heat to 55 C.for one hour with stirring, and cool to 50 C. Add 65.4 gm. (0.29M)3,4,5- trimethoxymethylbenzoate and heat to 60 C. for one hour tocomplete the reaction.

Pour the mixture onto 1100 gm. of ice and aqid fy with 180 ml. diluteI-ICl (1:1). Cool in an ice bath and filter the crystalline product.Wash with 2X 150 ml. of ice water and 2X 100 ml. ice cold lower alcoholsuch as ethanol. Air dry overnight or vacuum dry at 40 C. to constantweight. The yield will be 74 gm. of 88% of theory of suitableintermediate for the next step. A.N. Sample M.P. 147148 C.Recrystallized from ethanol. Calculated: C, 49.98; H, 5.59. Found: C,49.8; H, 5.54.

Example 96 Reduction of methyl-a-(3,4,S-trimethoxyacetophenone) sulphoneto the corresponding alcohol:

Set up a 3 neck 1 liter flask equipped with a stirrer in an ice 'bath.Charge with 38.1 gm. of methyl-a-(3,4,5-trimethoxyacetophenone)sulphone, 100 ml. desalted water and '30 ml. ethanol and cool thisslurry to +115 C. Add portion wise a precooled solution of 2 gm. sodiumborohydride in 40 ml. desalted water. The first few m1. will cause aslight foaming but it can be controlled easily with a few ml. ofethanol. Additional ethanol can be used to wash down the sides of thereaction flask.

At the end of the addition of the borohydride remove the cooling bathand stir for one hour. Completion of the reaction is checked by UV. Coolthe slurry to +2 C. and filter all solids. Wash with small amounts ofice water and dry in vacuum oven at 50 C. to constant weight. The yieldwill be 34.2 gm. or 89.3% of theory. A.N. Sample M.P. 153-l54 C.Recrystallized from ethanol. Calculated: C, 49.7; H, 6.24. Found: C,49.39; H, 6.27.

Example 97 w- (Methylsulfinyl) 3 ,4,S-Trimethoxyacetophenone:

Into a three necked flask, equipped with condenser, stirrer andthermometer, charge 4.0 gm. sodium amide (hexane washed) and 75 ml.dimethyl sulphoxide (distilled and dried). Slowly warm (in an externalWater bath) to 45 C. an the reaction begins. Raise temperature graduallyto 60 C. and maintain for one (1) hour, to complete. Cool to and adddropwise a solution of 12 gm. 3,4,5-trimethoxymethylbenzoate in 25 ml.of dimethylsulphoxide. Keep the temperature between -25 C. by externalcooling. Stir /2 hour at room temperature and quench into 300 ml. icewater. Carefully acidity to pH 5-6 with cold dilute hydrochloric acid.

Extract into chloroform 3 X 100 ml., wash the organic layer with 4X 50ml. water, dry over sodium sulphate, filter and flash evaporate allsolvent.

The heavy oil will weigh 15 gm. and slowly crystallize on standing.

To purify; dissolve the thick oil in 75 ml. ethyl acetate, charcoal andcool the filtrate in an ice acetone bath. Filter and dry the whitesolid. Wt.=l0 gm. -70% yield. M.P. 1l3-115 C. A.N. Sample M.P. 115-'116C. Recrystallized from acetone. Calculated: C, 53.05; H, 5.92. Found: C,52.69; H, 5.84.

Example 98 ,S-Hydroxy ,6 3,4,5 trimethoxyphenethylmethylsulphoxide:

Combine 14 gm. w-(methylsulfinyl)3,4,5-trimethoxyacetophenone, 50 ml.desalted Water and 35 ml. methanol. Cool to +15 C. and with magneticstirring add slowly a solution of 0.5 gm. sodium borohydricle in 10 ml.water. The reaction is exothermic but can be controlled between 15- 20C. with external cooling. Stir at room temperature for 2 hours, checkfor completion by UV. and finally strip otf methanol by vacuum at 45-50"C. Extract the aqueous solution with 3X 75 ml. chloroform, wash with theorganic layer 1X 75 ml. water, dry over magnesium sulphate, filter andevaporate to a clear thick oil. A few drops of ethyl acetate causescomplete crystallization. Weight=l4 gm. This is suitable for use in thenext step without further purification. A.N. Sample M.P. 150-155" C.(Isomers) Recrystallized from ethyl acetate. Calculated: C, 52.4; H,6.61. Found: 1 C, 52.37; H, 6.70.

Example 99' u- 3 ,4,5-Trimethoxybenzyl) B-anilinoacrylonitrile CHaOOHNHPh CH30 CH2O Combine in a flask at room temperature 5.4 gm.fl-hydroxy-B-3,4,5-trimethoxyphenethyl methyl sulphoxide, 3 gm.fl-anilinopropionitrile, 25 ml. dimethylsulphoxide and 2.0 gm. sodiummethylate. Warm slowly with stirring, on a steam bath up to -95 C. Itgets very dark in color. Reaction, by U.V., is complete in 20 minutes atC.

Quench in ice water and Wash the dark oily precipitate by decantation.Dissolve in 15 ml. of ethanol and cool. Filter the heavy yellowcrystalline precipitate, wash with cold ethanol and hexane. Dry. Wt.=2gm. -31% yield. The U.V., LR, and M.P. are identical to that preparedfrom the 3,4,S-trimethoxybenzaldehyde and ,B-anilinopropionitrile.Ph=pl1enyl.

Example a- (3,4,5 -Trimethoxybenzyl) -B-anilinoacrylonitrile omo CHNH Ph0 HaO- CH2 N H3O In a three neck flask equipped with stirrer, condenserand thermometer, charge 29 gm. J3hydroxy-B3,4,5-trimethoxyphenethylmethylsulphone, 16.5 gm.B-anilinopropionitrile and 40 ml. dimethylsulphoxide. Warm to 40 C. withstirring, and gradually add 83 m1. of a 13.6% solu tion of potassiumtertiary butoxide in tertiary butanol. Maintain internal temperature at45 C. for one hour and check for completion by UV.

Strip as much alcohol as possible by vacuum using an external water bath(70 'C.) and quench in ice water (200 ml.). Stir until the thick oilturns crystalline and filter. Wash the cake with ice water and finallyhexane. Vacuum dry at 35 C. to constant weight. The yield will be 32 gm.or theory of crude a-(3,4,5-trimethoxybenzyl- B-anilinoacrylonitrile).The =U.V. is satisfactory and it may be used directly in the preparationof Trimethoprim.

Example 101 Trimethoprim 2,4-diamino 5 (3',4',5trimethoxybenzyl)pyrimidine: Prepare a guanidine solution from 15Hexamethylphosphoramide has been substituted for the dimethylsulplioxide as well as potassium hydroxide in Inethanol for the sodiummethylate with the same results in all cases.

Recrystallisation: Dissolve the crude intermediate in 75 ml. hotethanol. Cool in ice/acetone bath (preferably overnight) and filter.Wash the cake with cold ethanol (1 5 ml.) and hexane. Vacuum dry.Weight=26+ gm.-80% yield.

gm. guanidine HCl, gm. sodium methylate, and 100 ml. ethanol. Cool,filter salt free, and combine with 16 gm. ot-(3,4,5-trimethoxybenzyl)fl-anilinoacrylonitrile. Reflux on a steam bath overnight, charcoal thehot solution with 2.0 gm. Darco 6-60 and evaporate to A volume. Cool tocomplete crystallization, filter, and wash with cold ethanol, acetone,and ether. Dry. Weight=13+ gm. -91% theory. M.P. 198200 C.

Example 102 B-Hydroxy B 3,4,5 trimethoxyphenethylmethylsulphoxide:Sodium methylate (5.4 gm.) was dissolved in hot dimethylsulfoxide (50ml.), the solution was cooled to room temperature,3,4,S-trimethoxybenzaldehyde (18 gm.) was added, and the mixture wasstirred at room temperature for 2 hours. Water (100 ml.) was then addedto the mixture which was next extracted with chloroform. The chloroformextract was washed with water, dried over anhydrous sodium sulfate, andevaporated to dryness. The residual yellow oil crystallised on additionof ethylacetate. The crystals were collected and Washed with pentane.Wt.=l4.8 gm. (59%) MP. l60l62 C. (After recrystallisation fromethylacetate.) LR. and UV. spectra in agreement with structure.Calculated: C, 52.4; H, 6.61. Found: C, 52.37; H, 6.70.

What we claim is:

1. The method of preparing a compound of formula I 1 R .t. /CN

ca c 5 4 CHI-N R 6 with guanid ine carbonate in a polar aprotic solventat an elevated temperature above room temperature to about 160 C.wherein R R are the same or difierent, and each is hydrogen, halogen,lower alkyl, lower alkoxy or benzyloxy, or R and (R taken together maybe methylenedioxy when both R and R are hydrogen, and wherein NR R isprimary amino or secondary amino of not less than one or more thantwelve carbon atoms selected from the group consisting ofmonoalkylamino, dialkylamino, anil'ino or naphthyl-amino wherein thephenyl or naphthyl thereof may be substituted with one or more positionswith lower alkyl, lower alkoxy and halogen, N- ethylanilino, pyrrolidino, piperidino N-metlhylanilino,

24 piperazino, benzylamino and morpholino, and wherein the lower alkyland lower alkoxy are each of 1 to 4 carbon atoms.

2. The method according to claim 1 in which R is selected from the groupconsisting of lower alkyl and phenyl or naphthyl substituted with one ormore lower alkyl, lower alkoxy, or halogen provided that the totalnumber of carbon atoms is between 6 to 12 and R is lower alkyl and mayalso be hydrogen when R is alkyl and NR R may also be cyclic amino,morpholino or benzylamino of 2 to 12 carbons.

3. The method according to claim 2 wherein the temperature is betweenabout C. to about C.

4. The method according to claim 3 wherein the solvent isdimethylsulfoxide, hexamethylphorphoramide and N 'N-dimethyl-aceta'mide.

5. The method according to claim 4 in which NR |R is morpholino,N-methyl an i-lino, piperidino, pyrrol idino, dimethyla'mino,benzyl-amino, and where the phenyl ring bearing R R is substituted withmethoxy at the 3, 4, 5 or 3, 4 position or is substituted with bromo atthe 5 position when methoxy is present at the 3 and 4 position.

6. The methanol according to claim 1 of preparing the compound 2,4diamino-S-(3',4',5'-trimethoxybenzyl)pyrimidine which comprises the stepof reacting a compound of the formula I with guanidine carbonate in apolar aprotic solvent at an elevated temperature above room temperatureto about 160 C.

7. The method of claim 6 in which the compound of formula I is selectedfrom the class consisting of fl-N- methylanilino oz3,4,5-trimethoxybenzylacrylonitrile, fipiperidino a 3,4,5trimethoxybenzylacrylonitrile,flpyrrolidino-u-I:,4,5-trimethoxybenzylacrylonitrile, pdimethylamino-3,4,5 trimethoxybenzylacrylonitrile, and B-'benzylamino-a-Il,4,5-trimethoxybenzylacrylonitrile.

8. The method of preparing 2,4-diamino-5-(3,4',5'-trimethoxybenzyl)pynimidine which comprises the step of reactingfi-morpholino-wit,4,S-trimethoxybenzylacrylonitrile with guanidinecarbonate in a polar aprotic solvent at an elevated temperature aboveroom temperature to about 160 C.

References Cited FOREIGN PATENTS 1,087,505 10/ 1967 Great Britain.

OTHER REFERENCES Parker: Advances in Organic Chemistry, Vol. 5 (1965),Intersoience Publishers, pp. 2-3, 9-10.

RAYMOND V. RUSH, Primary Examiner

1. THE METHOD OF PREPARING A COMPOUND OF FORMULA I